https://scholars.lib.ntu.edu.tw/handle/123456789/634543
標題: | Discovery of HDAC6, HDAC8, and 6/8 Inhibitors and Development of Cell-Based Drug Screening Models for the Treatment of TGF-β-Induced Idiopathic Pulmonary Fibrosis | 作者: | Yu, Wei-Chieh Yeh, Tsung-Yu Ye, Chih-Hung Chong, Patrick Chun Theng Ho, Yi-Hsun So, Dorothy Kazuno Yap, Kah Yi Peng, Guan-Ru Shao, Chi-Hsuan Jagtap, Ajit Dhananjay JI-WANG CHERN CHEN-SI LIN Lin, Shau-Ping SHUEI-LIONG LIN SHU-HAN YU CHAO-WU YU |
公開日期: | 10-八月-2023 | 卷: | 66 | 期: | 15 | 起(迄)頁: | 10528 | 來源出版物: | Journal of medicinal chemistry | 摘要: | Idiopathic pulmonary fibrosis is incurable, and its progression is difficult to control and thus can lead to pulmonary deterioration. Pan-histone deacetylase inhibitors such as SAHA have shown potential for modulating pulmonary fibrosis yet with off-target effects. Therefore, selective HDAC inhibitors would be beneficial for reducing side effects. Toward this goal, we designed and synthesized 24 novel HDAC6, HDAC8, or dual HDAC6/8 inhibitors and established a two-stage screening platform to rapidly screen for HDAC inhibitors that effectively mitigate TGF-β-induced pulmonary fibrosis. The first stage consisted of a mouse NIH-3T3 fibroblast prescreen and yielded five hits. In the second stage, human pulmonary fibroblasts (HPFs) were used, and four out of the five hits were tested for caco-2 permeability and liver microsome stability to give two potential leads: J27644 (15) and 20. This novel two-stage screen platform will accelerate the discovery and reduce the cost of developing HDAC inhibitors to mitigate TGF-β-induced pulmonary fibrosis. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/634543 | ISSN: | 00222623 | DOI: | 10.1021/acs.jmedchem.3c00644 |
顯示於: | 生物科技研究所 |
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